{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T08:04:42Z","timestamp":1790150682596,"version":"4.0.1"},"reference-count":57,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,11,17]],"date-time":"2013-11-17T00:00:00Z","timestamp":1384646400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2014,2]]},"abstract":"Summary<\/jats:title>Multiple myeloma, the second most common haematological malignancy in the U.S., is currently incurable. Disruption of the intrinsic apoptotic pathway by BCL<\/jats:styled-content>2 and MCL<\/jats:styled-content>1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL<\/jats:styled-content>2 or MCL<\/jats:styled-content>1. Thus, we investigated the anti\u2010tumour effects of a pan\u2010BCL<\/jats:styled-content>2 inhibitor, AT<\/jats:styled-content>\u2010101, which has high binding specificity for BCL<\/jats:styled-content>2 and MCL<\/jats:styled-content>1 in preclinical models of plasma cell cancers (M<\/jats:styled-content>ultiple myeloma and W<\/jats:styled-content>aldenstr\u00f6m macroglobulinaemia). Gene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of BCL<\/jats:styled-content>2 family members. AT<\/jats:styled-content>\u2010101 was able to downregulate BCL<\/jats:styled-content>2 and MCL<\/jats:styled-content>1 in all plasma cell cancer models and induced apoptotic cell death in a caspase\u2010dependent manner by altering mitochondrial membrane permeability. This cytotoxic effect and BCL<\/jats:styled-content>2 downregulation were further potentiated when AT<\/jats:styled-content>\u2010101 was combined with lenalidomide\/dexamethasone (LDA<\/jats:styled-content>). NanoString nCounter mRNA<\/jats:styled-content> quantification and I<\/jats:styled-content>ngenuity P<\/jats:styled-content>athways A<\/jats:styled-content>nalysis revealed differential changes in the CCNA<\/jats:styled-content>2, FRZB<\/jats:styled-content>, FYN<\/jats:styled-content>, IRF<\/jats:styled-content>1, PTPN<\/jats:styled-content>11<\/jats:italic> genes in LDA<\/jats:styled-content>\u2010treated cells. In summary, we describe for the first time the cellular and molecular events associated with the use of AT<\/jats:styled-content>\u2010101 in combination with lenalidomide\/dexamethasone in preclinical models of plasma cell malignancy.<\/jats:p>","DOI":"10.1111\/bjh.12633","type":"journal-article","created":{"date-parts":[[2013,11,18]],"date-time":"2013-11-18T06:04:40Z","timestamp":1384754680000},"page":"352-365","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["AT<\/scp>\u2010101 downregulates BCL<\/scp>2 and MCL<\/scp>1 and potentiates the cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma and W<\/scp>aldenstr\u00f6m macroglobulinaemia"],"prefix":"10.1111","volume":"164","author":[{"given":"Aneel","family":"Paulus","sequence":"first","affiliation":[{"name":"Department of Cancer Biology Mayo Clinic Jacksonville 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